Amorphous (5-fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid

Abstract

The invention relates to a stable amorphous form of (5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid and its use in the treatment of conditions mediated by the action of PGD 2 at the CRTH2 receptor.

The invention claimed is: 
     
       1. Amorphous (5-Fluoro-2-methyl-3-quinolin-2-ylmethyl-indol-1-yl)-acetic acid (Compound 1) or a pharmaceutically or veterinarily acceptable salt thereof. 
     
     
       2. A method for the treatment of a disease or condition selected from the group consisting of asthma, asthma exacerbations, chronic obstructive pulmonary disease, allergic rhinitis conjunctivitis, nasal polyps, atopic dermatitis, contact hypersensitivity, eosinophilic cough, eosinophilic bronchitis, eosinophilic gastroenteritis, eosinophilic oesophagitis, food allergies, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis, urticaria, hypereosinophilic syndrome, hyper IgE syndrome, infection, fibrotic diseases, Churg-Strauss syndrome, and multiple sclerosis, comprising administering to a patient in need of such treatment an effective amount of an amorphous form of Compound 1 or a pharmaceutically or veterinarily acceptable salt thereof. 
     
     
       3. A pharmaceutical or veterinary composition comprising amorphous Compound 1 or a pharmaceutically or veterinarily acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. 
     
     
       4. The composition as claimed in  claim 3 , further comprising one or more additional active agents selected from:
 Suplatast tosylate and similar compounds; 
 β2 adrenoreceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate and pirbuterol or methylxanthines such as theophylline, oxitriphylline and aminophylline, mast cell stabilisers such as sodium cromoglycate or muscarinic receptor antagonists such as tiotropium, aclidinium and ipratorium; 
 antihistamines, for example histamine H 1  receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine, olopatadine and chlorpheniramine or H 4  receptor antagonists; 
 α 1  and α 2  adrenoreceptor agonists such as propylhexedrine phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride and ethylnorepinephrine hydrochloride; 
 modulators of chemokine receptor function, for example CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C—C family) or CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C—X—C family) and CX 3 CR1 for the C—X 3 —C family; 
 Leukotriene antagonists such as montelukast, pranlukast and zafirlukast 
 leukotriene biosynthesis inhibitors such as 5-lipoxygenase inhibitors or 5-lipoxygenase activating protein (FLAP) inhibitors such as zileuton, atreleuton, fenleuton, tepoxalin, 1-[4-[5-(4-fluorophenoxy)furan-2-yl]but-3-yn-2-yl]1-hydroxyurea, N-(5-substituted)-thiophene-2-alkylsolfonamides, 2,6-di-tert-butylphenol hydrazones, methoxytetrahydropyrans such as 6-[[3-fluoro-5-(4-methoxyoxan-4-yl)phenoxy]methyl]-1-methylquinolin-2-one, 1-[(3S)-6-[(2,6-difluorophenyl)methoxy]-2,3-dihydro-1-benzofuran-3-yl]-1-hydroxyurea, pyridinyl-substituted-2-cyanonaphthalene compounds such as [1S,5R]-3-cyano-1-(3-furyl-6-{6-[3-(3α-hydroxy-6,8-dioxabicyclo[3.2.1]octanyl)]pyridin-2-ylmethoxy}naphthalene, 2-cyanoquinoline compounds such as [1S,5R]-2-cyano-4-(3-furyl)-7-3-fluoro-5-[3-(3α-hydroxy-6,8-dioxabicyclo[3.2.1]-octanyl)]phenoxymethyl quinoline, indole and quinolone compounds such as quiflapon, 1-[(4-chlorophenyl)methyl]-3-[(1,1-dimethylethyl)thio]-α,α-dimethyl-5-(1-methylethyl)-1H-indole-2-propanoic acid and (2R)-2-cyclopentyl-2-[(4-quinolin-2-ylmethoxy)phenyl]acetic acid; 
 Phosphodiesterase inhibitors, including PDE4 inhibitors such as roflumilast; 
 anti-IgE antibody therapies such as omalizumad; 
 anti-infectives such as fusidic acid (particularly for the treatment of atopic dermatitis); 
 anti-fungals such as clotrimazole (particular for the treatment of atopic dermatitis); 
 immunosuppressants such as tacrolimus and particularly pimecrolimus in the case of inflammatory skin disease or alternatively rapamycin, cyclosporine, azathioprine or methotrexate; 
 Immunotherapy agents including allergen immunotherapy such as Grazax; corticosteroids such as prednisone, prednisolone, flunisolide, ciclesonide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate mometasone furoate and fluticasone furoate; 
 drugs which promote Th1 cytokine response such as interferons, TNF or GM-CSF; and 
 therapies that are in development for inflammatory indications including: 
 other antagonists of PGD 2  acting at other receptors such as DP antogonists; 
 drugs that modulate cytokine production such as inbhitors of TNFα converting enzyme (TACE) anti-TNF monoclonal antibodies, TNF receptor immunoglobulin molecules, inhibitors of other TNF isoforms, non-selective COX-1/COX-2 inhibitors such as piroxicam, diclofenac, propionic acids such as naproxen, flubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefanamic acid, indomethacin, sulindac and apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin; COX-2 inhibitors such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib, low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold; 
 drugs that modulate the activity of Th2 cytokines including IL-4, IL-5, IL-9, IL-13 and their receptors, for example blocking monoclonal antibodies (e.g. mepolizumab) and soluble receptors; 
 PPAR-γ agonists such as rosiglitazone, piaglitazone; or with 
 anti-RSV antibodies such as Synagis (palivizumab) and agents that may be used to treat rhinovirus infection in the future e.g. interferon-alpha, interferon-beta or other interferons. 
 
     
     
       5. The composition as claimed in  claim 4 , wherein the additional active agent is selected from the group consisting of montelukast, pranlukast, zafirlukast, loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine, olopatadine, and chlorpheniramine. 
     
     
       6. A method for the treatment of a disease or condition selected from the group consisting of asthma, asthma exacerbations, chronic obstructive pulmonary disease, allergic rhinitis conjunctivitis, nasal polyps, atopic dermatitis, contact hypersensitivity, eosiniphilic cough, eosinophilic bronchitis, eosinophilic gastroenteritis, eosinophilic oesophagitis, food allergies, inflammatory bowel disease, ulcerative colitis, Crohn's disease, mastocytosis, urticaria, hypereosinophilic syndrome, hyper IgE syndrome, infection, fibrotic diseases, Churg-Strauss syndrome, and multiple sclerosis, comprising administering to patient in need of such treatment an amorphous Compound 1 or a pharmaceutically or veterinarily acceptable salt thereof and one or more of the agents listed in  claim 4 . 
     
     
       7. A kit for the treatment of a disease or condition mediated by the action of PGD 2  at the CRTH2 receptor comprising a first container comprising an amorphous Compound 1 or a pharmaceutically or veterinarily acceptable salt thereof and a second container comprising one or more of the active agents listed in  claim 4 .